2012年9月5日，日本最大的制药商——武田（Takeda）制药，与其合作伙伴NPS制药公司宣布，药物Revestive（teduglutide）上市许可申请（MAA）已获欧盟委员会批准，作为日服一次的药物用于短肠综合征（short bowel syndrome，SBS）成人患者的治疗。 在今年6月21日，Revestive的上市许可申请（MAA）已获欧洲药品管理局（EMA）人用医药产品委员会（CHMP）积极意见。 最初将通过NPP项目（Named Patient Program）向欧洲的患者提供Revestive。 “短肠综合征（SBS）患者遭受营养不良和腹泻，并经常需要胃肠外营养支持来维持生命，”丹麦哥本哈根大学医学院消化内科Palle Bekker Jeppesen医师说道。“对于我们的患者来说，Revestive是一种新颖、独特、重要的治疗选择，同时为有限的治疗医疗设备增加了重要的价值。” 欧洲获批的首个SBS药物 “Teduglutide是欧洲首个获批用于SBS的药物，为这一患者群体提供了一个新的、重要的治疗选择，”武田欧洲及加拿大商业运作中心主任Trevor Smith说道。 “Teduglutide欧洲上市申请的获批对于SBS患者来说是个大好消息，”NPS制药总裁兼CEO Francois Nader说道。“我们期待着与我们的合作伙伴武田一同协作，在欧洲市场推出这一重要产品。” Revestive的上市许可申请在欧盟成员国有效，预计冰岛及挪威的监管申请将在30天内获批。 此次获批，是基于一项关键性双盲、安慰剂对照的III期安全性及有效性试验，试验中的SBS患者均需要胃肠外营养支持。在试验中，43例患者接受皮下注射0.05mg/kg/day剂量的teduglutide，另外43例患者注射安慰剂，整个治疗周期为24周。 Teduglutide治疗组，在20周及24周时胃肠外营养支持减少20%~100%的患者比例，明显高于安慰剂组（60% vs 30%，p=0.002）。在24周内，teduglutide治疗患者胃肠外营养支持需求量减少达4.4升/周，而安慰剂组这一数据为2.2升/周。Teduglutide治疗组有21例患者取得了至少1天胃肠外应用支持的减少（54%），而安慰剂组仅为9例（23%）。研究中，在剂量、频率及持续方面，teduglutide均具有良好的耐受性。 Revestive 5 mg powder and solvent for injection In the EU, Revestive® 5 mg powder and solvent for injection is approved for the treatment of adult patients with Short Bowel Syndrome; patients should be stable following a period of intestinal adaptation after surgery. Expanded Access Aside from a clinical trial, a drug typically may not be distributed prior to its approval by government regulators, such as the US Food and Drug Administration or European Medicines Agency. However, there are rare exceptions for select patients with serious or immediately life-threatening diseases who have no comparable or suitable treatment alternatives. When this situation occurs in the US, FDA regulations allow access to investigational drugs for treatment purposes on a case-by-case basis for an individual patient, or for intermediate-size groups of patients with similar treatment needs who otherwise do not qualify to participate in a clinical trial2. Similarly, in the EU, Named Patient (or Compassionate Use) Programs create access to particular treatments prior to marketing authorization for patients with life-threatening, chronic or seriously disabling conditions. Compassionate use programs are coordinated and implemented by the EU Member States, which decide independently how and when to open such programs according to national rules and legislation. Abbreviated SPC Revestive 5 mg powder and solvent for solution for injection Summary of Product Characteristics (SPC) is available here. Therapeutic indications Revestive® (teduglutide) is indicated for the treatment of adult patients with Short Bowel Syndrome. Patients should be stable following a period of intestinal adaptation after surgery. Important Safety Information Posology Adults: The recommended dose of teduglutide is 0.05 mg/kg body weight once daily. Special populations Elderly: No dose adjustment is necessary in patients above the age of 65 years. Renal Impairment: No dose adjustment is necessary for patients with mild renal impairment. In patients with creatinine clearance less than 50 mL/min, the daily dose should be reduced by 50%. Hepatic Impairment: No dose adjustment is necessary for patients with mild and moderate hepatic impairment. Paediatric population: Revestive should not be used in children below 18 years old because of safety concerns. Contraindications Hypersensitivity to the active substance, excipients, or tetracycline. Active or suspected malignancy or a history of malignancies in the gastrointestinal tract or hepatobiliary system within the last five years. Special Warnings and Precautions for Use Intestinotrophic Effects Colo-rectal polyps: A colonoscopy with removal of polyps should be performed at the time of starting treatment and at a minimum of five year intervals with an individual assessment regarding frequency of surveillance based on the patient characteristics. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of malignancy, Revestive therapy should be discontinued. Gastrointestinal neoplasia including hepatobiliary tract: If a neoplasia is detected, it should be removed. In case of malignancy, Revestive therapy should be discontinued. Gallbladder and bile ducts: In case of gallbladder or bile duct-related symptoms, the need for continued Revestive treatment should be reassessed. Pancreatic diseases: In case of pancreatic adverse events, the need for continued Revestive treatment should be reassessed. Intestinal obstruction: In case of recurrent intestinal obstructions, the need for continued Revestive treatment should be reassessed. Increased Absorption Cardiovascular: Due to increased fluid absorption, patients with cardiovascular disease should be monitored with regard to fluid overload, especially during initiation of therapy. In case of a significant deterioration of the cardiovascular disease, the need for continued Revestive treatment should be reassessed. Concomitant treatment: Patients receiving oral concomitant medicinal products requiring titration or with a narrow therapeutic index should be monitored closely due to potential increased absorption. Discontinuation of treatment: Due to the risk of dehydration, discontinuation of treatment with Revestive should be managed carefully. Monitoring and Concomitant Diseases Monitoring of small bowel, gallbladder and bile ducts, and pancreas: SBS patients are to be kept under close surveillance. This usually includes the monitoring of short bowel function, gallbladder and bile ducts, and pancreas for signs and symptoms. Revestive Safety Information: Version: 001-0122014 Special clinical conditions: Revestive has not been studied in patients with severe, clinically unstable concomitant diseases or in patients with malignancies within the last five years. Caution should be exercised when prescribing Revestive. Hepatic impairment: Revestive has not been studied in patients with severe hepatic impairment. The data from use in subjects with moderate hepatic impairment do not suggest a need for restricted use. Excipients: Revestive contains less than 1mmol sodium (23 mg) per does. This means that it is essentially “sodium-free”. Caution is needed when administering Revestive to persons with a known hypersensitivity to tetracycline. Fertility, pregnancy and lactation There are no data from the use of Revestive in pregnant women. It is unknown whether teduglutide is excreted in human milk. There are no data on the effects of teduglutide on human fertility. As a precautionary measure, it is preferable to avoid the use of Revestive during pregnancy and breastfeeding. Effects on ability to drive and use machines Revestive has minor influence on the ability to drive and use machines. However, cases of syncope have been reported in clinical studies. Such events might impact the ability to drive and use machines. Undesirable effects The most commonly reported adverse reactions (≥ 10%) were abdominal pain and distension, respiratory tract infections, nausea, injection site reactions, headache, vomiting and oedema peripheral. Approximately 38% of the treated patients with a stoma experienced gastrointestinal stoma complications. Overdose In the event of an overdose, the patient should be carefully monitored by the medical professional Pharmacodynamic properties Teduglutide is an analogue of GLP-2. In several nonclinical studies, teduglutide has been shown to preserve mucosal integrity by promoting repair and normal growth of the intestine through an increase of villus height and crypt depth. List of excipients Powder: L-histidine, mannitol. sodium phosphate monohydrate, disodium phosphate heptahydrate, sodium hydroxide (pH adjustment); hydrochloric acid (pH adjustment) Solvent: Water for injections To report suspected adverse reactions, contact NPS Pharma Holdings Ltd at +800 67744357 Marketing Authorization Holder: NPS Pharma Holdings Limited ---------------------------------------------- New Drugs Online Report for teduglutide Information Generic Name: teduglutide   Trade Name: Revestive (EU), Gattex (US)  Synonym: ALX 0600, [gly2]-recombinant human glucagon-like peptide, Gattex  Entry Type: New molecular entity   Development and Regulatory status UK: Launched  EU: Launched  US: Launched  UK launch Plans: Available only to registered users Actual UK launch date: September 2014  Comments Sep 14: Launched in the UK. 5mg vial plus solvent, 28=£14,615.39 [33]. 17/09/2014 13:15:10  Mar 14: Marketed in the US [32] 24/03/2014 16:21:00  Nov 13: Supplemental New Drug Application submitted in the US to include long-term data from STEPS 2 in the product label. A decision by the FDA is expected by June 28, 2014 [31]. 17/11/2013 17:16:44  Aug 13: The company plans to launch in Europe in the first half of 2014 [29] 26/08/2013 11:02:53  Mar 13: NPS Pharmaceuticals has re-gained the full worldwide rights to teduglutide. The cost of teduglutide in the US is $295,000 a year. NPS will be marketing the drug in Europe [28]. 20/03/2013 19:28:06  Dec 12: Approved in US for the treatment of adult patients with short bowel syndrome who are dependent on parenteral support. Gattex will be available in Q1 2013. [27] 23/12/2012 19:01:28  Oct 12: FDA panel vote in favour of approval [26]. 18/10/2012 08:17:37  Oct 12: FDA staff issue a favourable review prior to the advisory panel meeting and endorse the company´s risk mitigation strategy. The FDA review notes that there are three key safety concerns, gastrointestinal obstructions, the growth of polyps and pancreatic disorders, but concludes that the drug´s use would not need to be restricted due to these concerns. Under the proposed REMS, doctors would be advised against prescribing the drug to any patient with active cancer, patients would need to be cancer-free for 5 years, all patients would have to undergo a colonoscopy within 6 months of beginning treatment and any polyps found should be removed during the procedure. A patient registry could gather long-term responses to the drug and, like most REMS programmes, physicians would need to complete an education program on risks. And the company proposes to help manage risk with a direct patient support programme [25]. 13/10/2012 17:15:42  Sep 12: Marketing authorisation approved in the EU [24]. 04/09/2012 21:23:32  Aug 12: Application will be discussed at the FDA´s Gastrointestinal Drugs Advisory Committee meeting scheduled for Oct 16, 2012 [23]. 28/08/2012 09:00:40  Aug 12: FDA decision date delayed to 30 Dec 12 [22]. 13/08/2012 16:45:58  Jun 12: EU positive opinion [21]. 22/06/2012 16:02:25  May 12: FDA decision expected by 28 Sep [20]. 16/05/2012 17:42:29  Jan 12: FDA has accepted and filed for review [19]. 01/02/2012 15:17:52  Dec 11: Company has completed the submission of a New Drug Application (NDA) to the FDA and has asked for a priority review [18]. 01/12/2011 21:58:54  Aug 11: Company has started a rolling submission of evidence to support the NDA in the US [16] 19/08/2011 12:43:48  March 11: Marketing Authorisation Application submitted to the EMA for approval of teduglutide as a once-daily subcutaneous treatment for short bowel syndrome (SBS). [14]  29/03/2011 10:19:11  Jan 11: Filing planned for 1H 2011 in EU and 2H 2011 in US [13].  31/01/2011 19:30:03  The US FDA recommended that the company should conduct a confirmatory PIII trial of teduglutide for SBS prior to the submission of a NDA for the drug. The STEPS trial is now underway (8). 24/03/2009 16:22:43  Orphan drug status in EU since Dec 01 (6) 11/04/2008 13:00:57  PIII in US with orphan drug status. Pivotal PIII study started in pts with short bowel syndrome (1).  Trial or other data Oct 13: New findings from STEPS 2, two-year open-label study: Investigators report long-term use of Gattex in pts with SBS resulted in additional, clinically meaningful reductions in the volume and days per week of parenteral support requirements in this extension study. In addition, 10 of the 13 pts who achieved complete independence from parenteral support were those who received 30 months of Gattex in the 6-month STEPS pivotal study and the 24-month STEPS 2 study. Two pts who received placebo in STEPS and 24 months of Gattex in STEPS 2 and one pt who bypassed STEPS and was enrolled directly into STEPS 2 also achieved independence from parenteral support. [3] 16/10/2013 15:50:26 Nov 11: In the STEPS 2 study, there were three cases of cancer, two of which resulted in death, reported at two sites in Poland. These cases have been reviewed by a safety review board & no changes in study design or current monitoring of subjects in the trial have been requested [17]. 02/11/2011 10:15:32 Oct 11: Data from long-term, open-label STEPS 2 study. Teduglutide was associated with achieving and maintaining clinically meaningful reductions in parenteral nutrition and IV fluid volume in adult subjects with short bowel syndrome. Primary study objective was to assess long-term safety and durability of effect in 76 subjects who completed, participated in, or qualified for participation in STEPS. 91% responded after 12 months of teduglutide, i.e. had a 20-100% reduction in PN/IV volume from baseline. 24% of subjects reduced their infusion days per week by 3 or more days after 12 months of therapy. Three subjects participating in STEPS 2 were able to gain complete independence from and discontinue PN/IV fluids. [16] 01/11/2011 08:47:00 Jan 11: The PIII pivotal STEPS study met the primary efficacy endpoint defined as the % of patients who achieved a ≥20% reduction in weekly PN volume at weeks 20 and 24 vs baseline. In an ITT analysis, 63% (27/43) of teduglutide-treated patients responded vs 30% (13/43) on placebo (p=0.002). Patients treated with teduglutide for 24 weeks also achieved significantly greater reductions in weekly PN volume (4.4L reduction from a pre-treatment baseline of 12.9L) vs placebo (2.3L reduction from a pre-treatment baseline of 13.2L (p ≤0.001). 4 of 86 randomized patients discontinued the study due to AEs (one on teduglutide and 3 on placebo) [13]. 31/01/2011 19:30:35 Jan 11: The PIII STEPS has completed the 24-week treatment period. NPS is also advancing STEPS 2, an open-label continuation study in which all participants will receive up to an additional 24 months of therapy. 97% of eligible patients who completed STEPS elected to enroll in STEPS 2 [12]. 14/01/2011 15:31:51 Jul 10: The confirmatory 24 week placebo-controlled study PIII STEPS study (NCT00798967) has completed its enrolment of 86 patients with parenteral nutrition-dependent short bowel syndrome. The study is due to complete Dec 10. The primary outcome is the proportion of patients who demonstrate a response (≥20% reduction in weekly parenteral nutrition volume) at week 20 and maintain that response to week 24. The company intend to report the results to the FDA early 2011 and file an NDA soon after [11]. 23/07/2010 21:53:00 Oct 09: Further results from the PIII study (n=83) were presented at the American College of Gastroenterology 2009 Meeting. Data from the 24-week study showed that teduglutide significantly improved lean body mass and total bone mineral content in PN-dependent SBS patients (Abstract P272). These effects are desirable as patients are prone to malnutrition, dehydration and osteoporosis. A separate presentation showed that teduglutide improves intestinal electrolyte and wet weight absorption in SBS patients. However, there was no significant correlation between these improvements and levels of plasma citrulline, which was being investigated as a biomarker of gut function (Abstract P273) [10]. 28/10/2009 08:43:13 Jun 09: The company expects to complete patient enrolment in the confirmatory PIII STEPS trial before the end of the Q1 2010 (9) 09/06/2009 17:59:01 Jun 09: Further data from the 24 week PIII study in 83 patients with SBS who were dependent on parenteral nutrition (PN) (described below) were presented at the Digestive Disease Week Congress. In the original analysis, teduglutide failed to meet its primary endpoint as the high dose arm (0.10mg/kg/day) did not reduce the need for PN by at least 20% vs. baseline to weeks 16 and weeks 24, although in the low dose arm (0.05mg/kg/day), 46% of patients achieved a statistically significant reduction of PN vs. placebo (p=0.007). The recent data include a study in a subpopulation of 21 patients in whom teduglutide decreased faecal wet weight by 735±574g/d vs. baseline (p=0.006), decreased sodium loss by 49±30 mm/L/day (p<0.001) and decreased potassium loss by 19±22 mm/L/d (p=0.003). In a second substudy, patients who exhibited an increase in endogenous non-protein amino-acid citrulline levels at week 8 were likely to achieve a significant response to teduglutide, suggesting that citrulline represents a good biomarker (9). 09/06/2009 17:58:49 Dec 08: STEPS (Study of TEduglutide in PN-dependent Short-bowel syndrome) PIII study in patients with SBS commenced. The study will have an initial three to eight week PN optimization and stabilization period, after which patients will be randomised to receive SC teduglutide 0.05 mg/kg or placebo daily for 24 weeks. The primary efficacy measure will be the percentage of patients who achieve a 20% or greater reduction in weekly PN volume at week 20 and maintain that response at week 24 compared with baseline (8).  24/03/2009 16:23:57 Oct 08: Results of a P3 28 wk, extension study presented at the American College of Gastroenterology Annual Scientific Meeting. The study enrolled 65 of 71 patients who had completed a 24-week randomised P3 study of low-dose teduglutide 0.05 mg/kg/day or high-dose teduglutide 0.10 mg/kg/day vs. placebo. Patients who received placebo in the original study received teduglutide in the extension study. There were no major differences in safety (primary endpoint) between groups except for a higher rate of injection site reactions with high-dose teduglutide. 12 of 16 patients, and 6 of 8 patients, who had responded to low-dose and high-dose teduglutide, respectively, maintained their response in the extension phase, with 10 and 2 patients, respectively, achieving further reductions in parenteral nutrition volumes. A mean weekly reduction in parenteral nutrition of 4.9L and 3.3L was achieved with low and high dose teduglutide (7). 19/10/2008 16:02:08 Failed to meet primary endpoint in clinical study but lower dose showed benefit (5) 27/03/2008 10:51:08 s.c. inj shown to stimulate intestinal lining growth and nutrient absorption. PIII studies designed to show reduction in use of IV feeding(2). 80 pts PIII double-blind efficacy study -randomised to receive 0.05 or 0.10 mg/kg/day of teduglutide, or a placebo for six months, with a six-month follow up study (3).  Evidence Based Evaluations FDA doc   EPAR NHSC  References   Available only to registered users